tbuckley/cabot-search huggingface dataset:
PKR induces TGF-β and limits oncolytic immune therapy
Authors: Bangxing Hong, Upasana Sahu, Matthew P Mullarkey, Evan Hong, Guangsheng Pei, Yuanqing Yan, Yoshihiro Otani, Yeshavanth Banasavadi-Siddegowda, Huihui Fan, Zhongming Zhao, Jianhua Yu, Michael A Caligiuri, Balveen Kaur
Journal: Journal for ImmunoTherapy of Cancer (2023)

Mammalian cells have developed multiple intracellular mechanisms to defend against viral infections. These include RNA-activated protein kinase (PKR), cyclic GMP-AMP synthase and stimulation of interferon genes (cGAS-STING) and toll-like receptor-myeloid differentiation primary response 88 (TLR-MyD88). Among these, we identified that PKR presents the most formidable barrier to oncolytic herpes simplex virus (oHSV) replication in vitro. To elucidate the impact of PKR on host responses to oncolytic therapy, we generated a novel oncolytic virus (oHSV-shPKR) which disables tumor intrinsic PKR signaling in infected tumor cells. As anticipated, oHSV-shPKR resulted in suppression of innate antiviral immunity and improves virus spread and tumor cell lysis both in vitro and in vivo. Single cell RNA sequencing combined with cell-cell communication analysis uncovered a strong correlation between PKR activation and transforming growth factor beta (TGF-ß) immune suppressive signaling in both human and preclinical models. Using a murine PKR targeting oHSV, we found that in immune-competent mice this virus could rewire the tumor immune microenvironment to increase the activation of antigen presentation and enhance tumor antigen-specific CD8 T cell expansion and activity. Further, a single intratumoral injection of oHSV-shPKR significantly improved the survival of mice bearing orthotopic glioblastoma. To our knowledge, this is the first report to identify dual and opposing roles of PKR wherein PKR activates antivirus innate immunity and induces TGF-ß signaling to inhibit antitumor adaptive immune responses. Thus, PKR represents the Achilles heel of oHSV therapy, restricting both viral replication and antitumor immunity, and an oncolytic virus that can target this pathway significantly improves response to virotherapy.
Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes
Authors: Santosh K. Panda, Vincent Peng, Raki Sudan, Alina Ulezko Antonova, Blanda Di Luccia, Takahiro E. Ohara, Jose Luis Fachi, Gary E. Grajales-Reyes, Natalia Jaeger, Tihana Trsan, Susan Gilfillan, Marina Cella, Marco Colonna
Journal: Immunity (2023)
Characteristics and Management of Ocular Involvement in Individuals with Monkeypox Disease
Authors: Marta Pazos, Josep Riera, Aina Moll-Udina, Alba Catala, Sofia Narvaez, Irene Fuertes, Marina Dotti-Boada, Gisela Petiti, Jordi Izquierdo-Serra, Enrique Maldonado, Meilin Chang-Sotomayor, David Garcia, Anna Camós-Carreras, Vanessa Gilera, Nicolas De Loredo, Jorge Peraza-Nieves, Nestor Ventura-Abreu, Felipe Spencer, Guillerima F. Del Carlo, Josep Torras, Josep Maria Nicolas, Alfredo Adán, Anna Vilella, Susana Puig, Esteban Martinez, Mikel J. Martinez, Bernardo Sánchez-Dalmau, José L. Blanco
Journal: Ophthalmology (2023)
Covid-19 and pregnancy
Journal: BMJ (2020)

Guideline: Coronavirus (COVID-19) Infection in pregnancy Published by the Royal College of Obstetricians and Gynaecologists (RCOG), with input from the Royal College of Midwives, the Royal College of Paediatrics and Child Health (RCPH), the Royal College of Anaesthetists, and the Obstetric Anaesthetists’ Association. This summary is based on version 8 of the guideline, published on 17 April 2020 ( https://www.rcog.org.uk/globalassets/documents/guidelines/2020-04-17-coronavirus-covid-19-infection-in-pregnancy.pdf )
Dual Functions of<i>labial</i>Resolve the Hox Logic of Chelicerate Head Segments
Authors: Guilherme Gainett, Benjamin C Klementz, Pola O Blaszczyk, Heather S Bruce, Nipam H Patel, Prashant P Sharma
Journal: Molecular Biology and Evolution (2023)

Despite an abundance of gene expression surveys, comparatively little is known about Hox gene function in Chelicerata. Previous investigations of paralogs of labial (lab) and Deformed (Dfd) in a spider have shown that these play a role in tissue maintenance of the pedipalp segment (lab-1) and in patterning the first walking leg identity (Dfd-1), respectively. However, extrapolations of these data across chelicerates are hindered by the existence of duplicated Hox genes in arachnopulmonates (e.g., spiders and scorpions), which have resulted from an ancient whole genome duplication (WGD) event. Here, we investigated the function of the single-copy ortholog of lab in the harvestman Phalangium opilio, an exemplar of a lineage that was not subject to this WGD. Embryonic RNA interference against lab resulted in two classes of phenotypes: homeotic transformations of pedipalps to chelicerae, as well as reduction and fusion of the pedipalp and leg 1 segments. To test for combinatorial function, we performed a double knockdown of lab and Dfd, which resulted in a homeotic transformation of both pedipalps and the first walking legs into cheliceral identity, whereas the second walking leg is transformed into a pedipalpal identity. Taken together, these results elucidate a model for the Hox logic of head segments in Chelicerata. To substantiate the validity of this model, we performed expression surveys for lab and Dfd paralogs in scorpions and horseshoe crabs. We show that repetition of morphologically similar appendages is correlated with uniform expression levels of the Hox genes lab and Dfd, irrespective of the number of gene copies.
Genes Vary Greatly in Their Propensity for Collateral Fitness Effects of Mutations
Authors: Jacob D Mehlhoff, Marc Ostermeier
Journal: Molecular Biology and Evolution (2023)

Mutations can have deleterious fitness effects when they decrease protein specific activity or decrease active protein abundance. Mutations will also be deleterious when they cause misfolding or misinteractions that are toxic to the cell (i.e., independent of whether the mutations affect specific activity and abundance). The extent to which protein evolution is shaped by these and other collateral fitness effects is unclear in part because little is known of their frequency and magnitude. Using deep mutational scanning (DMS), we previously found at least 42% of missense mutations in the TEM-1 β-lactamase antibiotic resistance gene cause deleterious collateral fitness effects. Here, we used DMS to comprehensively determine the collateral fitness effects of missense mutations in three genes encoding the antibiotic resistance proteins New Delhi metallo-β-lactamase (NDM-1), chloramphenicol acetyltransferase I (CAT-I), and 2″-aminoglycoside nucleotidyltransferase (AadB). AadB (20%), CAT-I (0.9%), and NDM-1 (0.2%) were less susceptible to deleterious collateral fitness effects than TEM-1 (42%) indicating that genes have different propensities for these effects. As was observed with TEM-1, all the studied deleterious aadB mutants increased aggregation. However, aggregation did not correlate with collateral fitness effects for many of the deleterious mutants of CAT-I and NDM-1. Select deleterious mutants caused unexpected phenotypes to emerge. The introduction of internal start codons in CAT-1 caused loss of the episome and a mutation in aadB made its cognate antibiotic essential for growth. Our study illustrates how the complexity of the cell provides a rich environment for collateral fitness effects and new phenotypes to emerge.
The effect of caffeine on subsequent sleep: A systematic review and meta-analysis
Authors: Carissa Gardiner, Jonathon Weakley, Louise M. Burke, Gregory D. Roach, Charli Sargent, Nirav Maniar, Andrew Townshend, Shona L. Halson
Journal: Sleep Medicine Reviews (2023)

The consumption of caffeine in response to insufficient sleep may impair the onset and maintenance of subsequent sleep. This systematic review and meta-analysis investigated the effect of caffeine on the characteristics of night-time sleep, with the intent to identify the time after which caffeine should not be consumed prior to bedtime. A systematic search of the literature was undertaken with 24 studies included in the analysis. Caffeine consumption reduced total sleep time by 45 min and sleep efficiency by 7%, with an increase in sleep onset latency of 9 min and wake after sleep onset of 12 min. Duration (+6.1 min) and proportion (+1.7%) of light sleep (N1) increased with caffeine intake and the duration (-11.4 min) and proportion (-1.4%) of deep sleep (N3 and N4) decreased with caffeine intake. To avoid reductions in total sleep time, coffee (107 mg per 250 mL) should be consumed at least 8.8 h prior to bedtime and a standard serve of pre-workout supplement (217.5 mg) should be consumed at least 13.2 h prior to bedtime. The results of the present study provide evidence-based guidance for the appropriate consumption of caffeine to mitigate the deleterious effects on sleep.
Loosening the leash: The unique emotional canvas of human screams
Authors: Harold Gouzoules, Jonathan W. M. Engelberg, Jay W. Schwartz
Journal: Behavioral and Brain Sciences (2023)

Abstract We use screams to explore ideas presented in the target article. Evolving first in animals as a response to predation, screams reveal more complex social use in nonhuman primates and, in humans, uniquely, are associated with a much greater variety of emotional contexts including fear, anger, surprise, and happiness. This expansion, and the potential for manipulation, promotes listener social vigilance.
The central problem is still evolutionary stability
Authors: Sławomir Wacewicz, Przemysław Żywiczyński
Journal: Behavioral and Brain Sciences (2023)

Abstract We applaud Heintz &amp; Scott-Phillips's guiding metaphor of “unleashing leashed expression,” and we value the unified explanation for the emergence of not only language, but also other forms of unleashed expression, such as multimodal communication. We are more critical of the authors' discussion of the selection pressures acting towards unleashed expression, which are proposed to hinge on partner choice ecology.
Feasibility of Left Ventricle Ejection Fraction Calculation Using Electrocardiographically Gated SPECT Acquisition of 99mTc-HDP Bone Scintigraphy in Cardiac Amyloidosis
Authors: Erik T. te Beek, Albert Lafeber, Jan W.A. Postema, Jan Constandse, Eelko Ronner, Marc R.J. ten Broek
Journal: Clinical Nuclear Medicine (2023)

We performed bone scintigraphy in 6 patients with suspected cardiac amyloidosis. To evaluate feasibility of left ventricle function analysis, we additionally performed electrocardiographically gated SPECT acquisition. The cardiac-gated SPECT data confirmed adequate tracer uptake for automatic myocardial contour determination. LVEF estimations ranged between 24% and 54%. Comparison with LVEF estimations from prior echocardiography generally showed only small differences. In one patient, the LVEF measurements from both methods seemed discordant, probably reflecting actual LVEF worsening, which was confirmed at follow-up echocardiography. Therefore, our results may suggest that cardiac-gated SPECT acquisition at bone scintigraphy can provide meaningful estimates of LVEF.
Association of Hypertensive Disorders of Pregnancy With Future Cardiovascular Disease
Authors: Bilal Rayes, Maddalena Ardissino, Eric A. W. Slob, Kiran Haresh Kumar Patel, Joanna Girling, Fu Siong Ng
Journal: JAMA Network Open (2023)

Importance Hypertensive disorders in pregnancy (HDPs) are major causes of maternal and fetal morbidity and are observationally associated with future maternal risk of cardiovascular disease. However, observational results may be subject to residual confounding and bias. Objective To investigate the association of HDPs with multiple cardiovascular diseases. Design, Setting, and Participants A genome-wide genetic association study using mendelian randomization (MR) was performed from February 16 to March 4, 2022. Primary analysis was conducted using inverse-variance-weighted MR. Mediation analyses were performed using a multivariable MR framework. All studies included patients predominantly of European ancestry. Female-specific summary-level data from FinnGen (sixth release). Exposures Uncorrelated ( r 2 &amp;amp;lt;0.001) single-nucleotide variants (SNVs) were selected as instrumental variants from the FinnGen consortium summary statistics for exposures of any HDP, gestational hypertension, and preeclampsia or eclampsia. Main Outcomes and Measures Genetic association estimates for outcomes were extracted from genome-wide association studies of 122 733 cases for coronary artery disease, 34 217 cases for ischemic stroke, 47 309 cases for heart failure, and 60 620 cases for atrial fibrillation. Results Genetically predicted HDPs were associated with a higher risk of coronary artery disease (odds ratio [OR], 1.24; 95% CI, 1.08-1.43; P = .002); this association was evident for both gestational hypertension (OR, 1.08; 95% CI, 1.00-1.17; P = .04) and preeclampsia/eclampsia (OR, 1.06; 95% CI, 1.01-1.12; P = .03). Genetically predicted HDPs were also associated with a higher risk of ischemic stroke (OR, 1.27; 95% CI, 1.12-1.44; P = 2.87 × 10 −4 ). Mediation analysis revealed a partial attenuation of the effect of HDPs on coronary artery disease after adjustment for systolic blood pressure (total effect OR, 1.24; direct effect OR, 1.10; 95% CI, 1.02-1.08; P = .02) and type 2 diabetes (total effect OR, 1.24; direct effect OR, 1.16; 95% CI, 1.04-1.29; P = .008). No associations were noted between genetically predicted HDPs and heart failure (OR, 0.97; 95% CI, 0.76-1.23; P = .79) or atrial fibrillation (OR, 1.11; 95% CI, 0.65-1.88; P = .71). Conclusions and Relevance The findings of this study provide genetic evidence supporting an association between HDPs and higher risk of coronary artery disease and stroke, which is only partially mediated by cardiometabolic factors. This supports classification of HDPs as risk factors for cardiovascular disease.
Cancer-cell-derived sialylated IgG as a novel biomarker for predicting poor pathological response to neoadjuvant therapy and prognosis in pancreatic cancer
Authors: Ming Cui, Sami Shoucair, Quan Liao, Xiaoyan Qiu, Benedict Kinny-Köster, Joseph R. Habib, Elie M. Ghabi, Junke Wang, Eun Ji Shin, Sean X. Leng, Syed Z. Ali, Elizabeth D. Thompson, Jacquelyn W. Zimmerman, Christopher R. Shubert, Kelly J. Lafaro, Richard A. Burkhart, William R. Burns, Lei Zheng, Jin He, Yupei Zhao, Christopher L. Wolfgang, Jun Yu
Journal: International Journal of Surgery (2023)

Background: Neoadjuvant therapy (NAT) is increasingly applied in pancreatic ductal adenocarcinoma (PDAC); however, accurate prediction of therapeutic response to NAT remains a pressing clinical challenge. Cancer-cell-derived sialylated immunoglobulin G (SIA-IgG) was previously identified as a prognostic biomarker in PDAC. This study aims to explore whether SIA-IgG expression in treatment-naïve fine needle aspirate (FNA) biopsy specimens could predict the pathological response (PR) to NAT for PDAC. Methods: Endoscopic ultrasonography-guided FNA biopsy specimens prior to NAT were prospectively obtained from 72 patients with PDAC at the Johns Hopkins Hospital. SIA-IgG expression of PDAC specimens was assessed by immunohistochemistry. Associations between SIA-IgG expression and PR, as well as patient prognosis, were analyzed. A second cohort enrolling surgically resected primary tumor specimens from 79 patients with PDAC was used to validate the prognostic value of SIA-IgG expression. Results: SIA-IgG was expressed in 58.3% of treatment-naïve FNA biopsies. Positive SIA-IgG expression at diagnosis was associated with unfavorable PR and can serve as an independent predictor of PR. The sensitivity and specificity of SIA-IgG expression in FNA specimens in predicting an unfavorable PR were 63.9% and 80.6%, respectively. Both positive SIA-IgG expression in treatment-naïve FNA specimens and high SIA-IgG expression in surgically resected primary tumor specimens were significantly associated with shorter survival. Conclusions: Assessment of SIA-IgG on FNA specimens prior to NAT may help predict PR for PDAC. Additionally, SIA-IgG expression in treatment-naïve FNA specimens and surgically resected primary tumor specimens were predictive of the prognosis for PDAC.
Dysregulation of Mitochondrial Translation Caused by<i>CBFB</i>Deficiency Cooperates with Mutant PIK3CA and Is a Vulnerability in Breast Cancer
Authors: Navdeep Malik, Young-Im Kim, Hualong Yan, Yu-Chou Tseng, Wendy du Bois, Gamze Ayaz, Andy D. Tran, Laura Vera-Ramirez, Howard Yang, Aleksandra M. Michalowski, Michael Kruhlak, Maxwell Lee, Kent W. Hunter, Jing Huang
Journal: Cancer Research (2023)

Understanding functional interactions between cancer mutations is an attractive strategy for discovering unappreciated cancer pathways and developing new combination therapies to improve personalized treatment. However, distinguishing driver gene pairs from passenger pairs remains challenging. Here, we designed an integrated omics approach to identify driver gene pairs by leveraging genetic interaction analyses of top mutated breast cancer genes and the proteomics interactome data of their encoded proteins. This approach identified that PIK3CA oncogenic gain-of-function (GOF) and CBFB loss-of-function (LOF) mutations cooperate to promote breast tumor progression in both mice and humans. The transcription factor CBFB localized to mitochondria and moonlighted in translating the mitochondrial genome. Mechanistically, CBFB enhanced the binding of mitochondrial mRNAs to TUFM, a mitochondrial translation elongation factor. Independent of mutant PI3K, mitochondrial translation defects caused by CBFB LOF led to multiple metabolic reprogramming events, including defective oxidative phosphorylation, the Warburg effect, and autophagy/mitophagy addiction. Furthermore, autophagy and PI3K inhibitors synergistically killed breast cancer cells and impaired the growth of breast tumors, including patient-derived xenografts carrying CBFB LOF and PIK3CA GOF mutations. Thus, our study offers mechanistic insights into the functional interaction between mutant PI3K and mitochondrial translation dysregulation in breast cancer progression and provides a strong preclinical rationale for combining autophagy and PI3K inhibitors in precision medicine for breast cancer.CBFB-regulated mitochondrial translation is a regulatory step in breast cancer metabolism and synergizes with mutant PI3K in breast cancer progression.
Introducing the <i>JAMA Dermatology</i> Editorial Fellowship
Authors: Mya L. Roberson, Kanade Shinkai
Journal: JAMA Dermatology (2023)

As a commitment to elevating early-career academic dermatologists, JAMA Dermatology is seeking applications for a 2-year editorial fellowship position.The selected fellow will receive mentorship from the Editor around editorial processes and the functions of a clinical dermatology journal.The goal of this fellowship is to support the development of an early-career academic dermatologist to equip them with the skills to take on editorial responsibilities in a dermatology peer-reviewed journal at the conclusion of the
Comparison of 18F-FDG and 68Ga-FAPI-04 Uptake in Postoperative Re-evaluation of Gastric, Duodenal, and Colorectal Cancers
Authors: Huipan Liu, Xiao Yang, Lin Liu, Gengcuo Qu, Yue Chen
Journal: Clinical Nuclear Medicine (2023)

To compare the potential efficacy of 68 Ga-FAPI-04 PET/CT with that of 18 F-FDG PET/CT for detecting tumor recurrence and nodal and distant metastases in gastric, duodenal, and colorectal cancers.This single-center retrospective clinical study was performed at the Affiliated Hospital of Southwest Medical University between January 2020 and June 2022. Participants with gastric, duodenal, and colorectal cancers after curative resection underwent both 68 Ga-FAPI-04 and 18 F-FDG PET/CT. Histopathologic examination, morphologic imaging, and/or follow-up imaging served as the reference standards. The SUV max of the tumor recurrence and nodal and distant metastases between 18 F-FDG and 68 Ga-FAPI-04 PET/CT were compared using the paired-sample t test.Forty-one participants with gastric, duodenal, and colorectal cancers were enrolled in the study (median age, 51 years; range, 19-75 years). The sensitivity of 68 Ga-FAPI-04 PET/CT was higher than that of 18 F-FDG PET/CT for detecting tumor recurrence (6 of 6 [100%] vs 4 of 6 [67%]), nodal metastases (92 of 92 [100%] vs 31 of 92 [34%]), and distant metastases (28 of 30 [93%] vs 20 of 30 [67%]).68 Ga-FAPI-04 PET/CT for tumor re-evaluation showed potential for more accurate performance of gastric, duodenal, and colorectal cancers, thereby improving treatment decision-making.
Metarepresentation, trust, and “unleashed expression”
Authors: Leda Berio, Albert Newen, Richard Moore
Journal: Behavioral and Brain Sciences (2023)

Abstract Heintz &amp; Scott-Phillips's account of human expression leaves a number of central issues unclear – not least, whether the lack of expression in nonhuman species is attributable to their lack of the relevant metarepresentational abilities, an absence of trust, or a consequence of other factors. In place of their view, we propose a gradualistic account of the origins of human expression.
Three-dimensional technologies in presurgical planning of bone surgeries: current evidence and future perspectives
Authors: Yotam Portnoy, Jonathan Koren, Amal Khoury, Shai Factor, Solomon Dadia, Yuval Ran, Amit Benady
Journal: International Journal of Surgery (2023)

Background: The recent development of three-dimensional (3D) technologies introduces a novel set of opportunities to the medical field in general, and specifically to surgery. The preoperative phase has proven to be a critical factor in surgical success. Utilization of 3D technologies has the potential to improve preoperative planning and overall surgical outcomes. In this narrative review article, the authors describe existing clinical data pertaining to the current use of 3D printing, virtual reality, and augmented reality in the preoperative phase of bone surgery. Methods: The methodology included keyword-based literature search in PubMed and Google Scholar for original articles published between 2014 and 2022. After excluding studies performed in nonbone surgery disciplines, data from 61 studies of five different surgical disciplines were processed to be included in this narrative review. Results: Among the mentioned technologies, 3D printing is currently the most advanced in terms of clinical use, predominantly creating anatomical models and patient-specific instruments that provide high-quality operative preparation. Virtual reality allows to set a surgical plan and to further simulate the procedure via a 2D screen or head mounted display. Augmented reality is found to be useful for surgical simulation upon 3D printed anatomical models or virtual phantoms. Conclusions: Overall, 3D technologies are gradually becoming an integral part of a surgeon’s preoperative toolbox, allowing for increased surgical accuracy and reduction of operation time, mainly in complex and unique surgical cases. This may eventually lead to improved surgical outcomes, thereby optimizing the personalized surgical approach.
On the murky dissociation between expression and communication
Authors: Elizabeth Warren, Josep Call, György Gergely
Journal: Behavioral and Brain Sciences (2023)

Abstract The authors present an ambitious attempt to outline the gradual evolution of the cognitive foundations of ostensive communication. We focus on three problematic aspects of the distinction between expression and communication : ambiguity in the distinction's central principle of “complementary mechanisms,” inconsistencies in the application of the distinction across taxa, and the dismissal of mentalizing in nonhuman primates.